Vitamin C (ascorbic acid) physiology

摘要 与缺乏模型相比，浓度-函数法是确定人类维生素摄入量建议的更合理的方法。维生素C被用作这项工作的模型维生素。浓度-函数方法关键依赖于对维生素C生物化学和分子生物学、维生素C临床药代动力学和维生素C生理学的了解。 为了研究人体中维生素C的浓度-功能和生理关系，有必要选择容易获得的、含有维生素C的、以及维生素C浓度变化可能影响生理和/或细胞功能的临床样本。出于这些原因，我们把重点放在了人类红细胞上。作为前提，我们开发了一种新的方法来测量人红细胞中的维生素C。该方法为探索红细胞中维生素C在健康和疾病中的新功能奠定了基础。 与大多数动物不同，人类不能合成维生素C，而必须从饮食中获得。每天至少吃5份水果和蔬菜的健康人将获得200毫克或更多的维生素C，这将产生每升70-80微克的稳态空腹血浆浓度。从食物中摄取更多的维生素C不会产生更高的浓度。即使服用维生素C补充剂，血浆浓度也只会短暂上升。除红细胞外，所有组织都会积累维生素C，而不是血浆中的维生素C浓度。然而，一旦血浆浓度达到每升50到60微克分子，组织浓度就会饱和，不会进一步上升。因此，维生素C浓度受到严格控制。 为什么会出现严格的控制尚不清楚。我们推测，一种解释是，如果血浆浓度较高，严格控制血浆浓度可以促进维生素的旁分泌或局部作用。 为了验证这一假设，我们调查了人类肾上腺是否存在维生素C的旁分泌。作为对醛固酮增多症患者诊断评估的一部分，我们对26名患者静脉注射促肾上腺皮质激素。放射学引导下双侧肾上腺静脉置管，注射促肾上腺皮质激素后取肾上腺和外周血样。测定了47条肾上腺静脉和26条外周静脉的维生素C和皮质醇浓度。 服用促肾上腺皮质激素后，所有病例的肾上腺静脉维生素C浓度均升高。促肾上腺皮质激素后1~4分钟，平均峰值升至176+/-71umoles/L，周边值不变，仍为35+/-15umoles/L。促肾上腺皮质激素后15分钟，肾上腺静脉维生素C浓度几乎降至基线水平。在所有病例中，肾上腺静脉维生素C的释放先于皮质醇的释放。这些发现具有统计学意义，差异的p值为0.0001。 这些数据是在ACTH刺激前后同时测定肾上腺静脉外周维生素C浓度的所有物种中的第一个；是第一个证明分泌的维生素C的功能一定是局部的而不是全身的；也是第一个在人类中由激素调节的维生素分泌的例子。这些数据表明，人类肾上腺维生素C的释放是应激反应的组成部分。这些数据证实了这样一个假设，即严格控制维生素C浓度的一个原因是促进旁分泌功能。分泌的维生素C在肾上腺中的功能尚不清楚，将是未来研究的主题。

Summary Rather than deficiency models, a concentration-function approach is a more rational approach to determine vitamin intake recommendations for humans. Vitamin C is used as a model vitamin for this work. A concentration-function approach is critically dependent on understanding vitamin C biochemistry and molecular biology; vitamin C clinical pharmacokinetics; and vitamin C physiology. To study concentration-function and physiology relationships in humans for vitamin C, it is necessary to choose clinical samples that can be obtained easily; that contain the vitamin; and where changes in vitamin C concentration may affect physiology and/or cell function. For these reasons, we focused on human red blood cells. As a prerequisite, we developed a new method to measure vitamin C in human red blood cells. This method is the foundation for exploring new functions of vitamin C in red blood cells in health and disease. Humans, unlike most animals, cannot synthesize vitamin C and instead must obtain it from diet. Healthy humans who eat at least 5 servings of fruits and vegetables daily will obtain 200 mg or more of vitamin C. This will produce steady-state fasting plasma concentrations of 70 -80 umoles per liter. Ingestion of more vitamin C from foods will not produce higher concentrations. Even if a vitamin C supplement is taken, plasma concentrations will only rise transiently. All tissues, except red cells, accumulate vitamin C against its plasma concentration. However, once plasma concentrations reach 50 to 60 umoles per liter, tissue concentrations are saturated and do not rise further. Thus, vitamin C concentrations are tightly controlled. Why tight control occurs is unknown. We postulated that one explanation is that tight control of plasma concentrations could facilitate paracrine, or local, actions of the vitamin, if such concentrations were higher. To test this hypothesis, we investigated whether paracrine secretion of vitamin C occurs from adrenal glands in humans. As part of the diagnostic evaluation of patients with hyperaldosteronism, we administered adrenocorticotrophic hormone intravenously to 26 patients. Under radiographic guidance, catheters were placed in both adrenal veins, and adrenal and peripheral blood samples were taken after adrenocorticotrophic hormone was administered. Vitamin C and cortisol concentrations were measured in 47 adrenal veins and 26 peripheral veins. Following adrenocorticotrophic hormone, adrenal vein vitamin C concentrations increased in all cases. The mean peak value increased to 176 +/- 71 umoles per liter, reached between 1 and 4 minutes after adrenocorticotrophic hormone, while peripheral values were unchanged at 35 +/- 15 umoles per liter. Adrenal vein vitamin C concentrations declined nearly to baseline 15 minutes after adrenocorticotrophic hormone. In all cases, adrenal vein vitamin C release preceded cortisol release. The findings were statistically significant with p values for differences < 0.0001. These data are the first description in any species of simultaneous adrenal vein peripheral vitamin C concentrations before and after ACTH stimulation; are the first demonstration that the function of secreted vitamin C must be local rather than systemic; and are the first example of hormone mediated secretion of any vitamin in humans. The data indicate that adrenal vitamin C release in humans is an integral part of the stress response. The data validate the hypothesis that one reason for tight control of vitamin C concentrations is to facilitate a paracrine function. The function of secreted vitamin C in adrenals is unknown, and will be the subject of future research.